DRUG NAME Letrozole - BC Cancer

1 Letrozole drug NAME: Letrozole SYNONYM(S): Letzazole, CGS 20267 COMMON TRADE NAME(S): FEMARA (notice of compliance,1 May 1997; patent expires 2 April 2010) CLASSIFICATION: Aromatase inhibitor Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Letrozole is a reversible (Type II), nonsteroidal aromatase inhibitor. Aromatase catalyzes the final and rate-limiting step in the conversion of androgens to estrogens in peripheral tissues. This occurs mainly in adipose tissue, but also in normal and malignant breast tissues, and provides the main source of estrogen in postmenopausal women. The goal of hormone therapy in breast Cancer is to deprive tumour cells of estrogens, which are implicated in the development or progression of ,4 Maximal estrogen suppression is produced by a mg dose,3,5 although a higher dose (ie, mg per day) was associated with increased clinical Maximal estrogen suppression occurs 48-78 hours after a single Highly selective blockade of aromatase does not interfere with the production of other steroids (eg, adrenal corticosteroids, aldosterone)7,8 or thyroid stimulating Letrozole does not have progestogenic, androgenic or estrogenic ,8 Differences in the mechanism of action may contribute to the apparent lack of cross-resistance between steroidal (eg, exemestane) and nonsteroidal (eg, anastrozole, Letrozole ) aromatase PHARMACOKINETICS.

2 Interpatient variability no information found rapidly and completely absorbed10; food decreases Oral Absorption time to peak plasma concentration 1 h under fasting condition and 2 h after eating11 rapid, extensive distribution into level 7 times higher than the level after a single dose and achieved after 2-6 weeks. cross blood brain barrier? no information found volume of distribution L/kg 10 Distribution plasma protein binding 60% metabolized by hepatic cytochrome P450 (3A4 and 2A6 ) active metabolite(s) none Metabolism inactive metabolite(s) CGP 44645 mainly renal excretion urine 6% as unchanged; 84% as metabolites12 terminal half life 48 h Excretion clearance10 L/h Gender no information found Elderly no clinically significant difference13 Children no information found Ethnicity no information found Adapted from reference6 unless specified otherwise.

3 BCCancer Agency Cancer drug Manual Developed: 2001 Page 1 of 5 Letrozole Limited revision: 1 May 2006; 1 November 2010, 1 April 2011 Letrozole USES: Primary uses: Breast cancer14-16 *Health Canada Therapeutic Products Programme approved indication No pediatric indications. SPECIAL PRECAUTIONS: Carcinogenicity: Letrozole caused benign ovarian stromal tumours and hepatocellular adenoma and carcinoma in animal Mutagenicity: Not mutagenic in Ames test. Letrozole is clastogenic in mammalian in vitro but not in vivo chromosome ,13 Fertility: Letrozole caused sexual inactivity and atrophy of the reproductive tract in animal Pregnancy: FDA Pregnancy Category There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

4 Breastfeeding is not recommended due to the potential secretion into breast SIDE EFFECTS: The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug . Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically ORGAN SITE SIDE EFFECT Clinically important side effects are in bold, italics cardiovascular events (4%)18 peripheral edema (9-17%)18 cardiovascular (general) phlebitis/thromboembolism ( ) fatigue (11-30%)18 sweating (1-22%)18 constitutional symptoms weight gain (6%) hair thinning (3%) dermatology/skin rash (6%) endocrine hot flashes (6-47%)18 emetogenic potential: non-emetogenic14,15 anorexia (5%) constipation (8-10%)18 gastrointestinal diarrhea (6%) BCCancer Agency Cancer drug Manual Developed: 2001 Page 2 of 5 Letrozole Limited revision: 1 May 2006.

5 1 November 2010, 1 April 2011 Letrozole BCCancer Agency Cancer drug Manual Developed: 2001 Page 3 of 5 Letrozole Limited revision: 1 May 2006; 1 November 2010, 1 April 2011 ORGAN SITE SIDE EFFECT Clinically important side effects are in bold, italics dyspepsia (5%) increased appetite (1%) nausea (11%) vomiting (8%) hemorrhage vaginal bleeding (2-4%)18 hepatic elevated gamma-glutamyltransferase (4%) metabolic/laboratory hypercholesterolemia (4-12%)15,18 arthritis (6%)18 fracture (4%)18 musculoskeletal osteoporosis (6%)18 dizziness (3-12%)18 insomnia (3%) neurology somnolence (3%) 15 abdominal pain (6%) arthralgia/myalgia (12-21%)18 chest pain (7%) headache (13-18%)18 pain musculoskeletal pain (arms, legs, back) (27%) cough (8%) pulmonary dyspnea (9%) vaginal bleeding (see under hemorrhage ) sexual/reproductive function vaginal discharge (2%)

6 Adapted from reference14 unless specified otherwise. INTERACTIONS: AGENT EFFECT MECHANISM MANAGEMENT estrogen (estrogen replacement therapy, Premarin, , Estracomb, Estraderm) may interfere with therapeutic effect of Letrozole estrogen can counter the estrogen suppression effect of Letrozole see below Letrozole BCCancer Agency Cancer drug Manual Developed: 2001 Page 4 of 5 Letrozole Limited revision: 1 May 2006; 1 November 2010, 1 April 2011 AGENT EFFECT MECHANISM MANAGEMENT tamoxifen tamoxifen decreases plasma Letrozole level by 38%, but has no significant effect on estrogen suppression by letrozole19; Letrozole has no effects on the pharmacokinetics of tamoxifen and its major metabolites20 possibly increased Letrozole metabolism by inducing cytochrome P450 3A4 avoid concurrent therapy outside clinical trials Estrogen use with Letrozole : use other options for conditions in which estrogen is indicated.

7 If estrogen is used, prescribe the lowest dose to relieve symptoms, monitor patient carefully and consider short term For vaginal complaints such as dyspareunia, dryness and sexual dysfunction, topical estrogen may be considered. Estring produces a local effect with systemic levels measurable only for the first 24 hours of the three month ring. Premarin cream can be used but may have variable systemic levels related to the absorption through the vaginal tissues. The lowest dose to relieve symptoms should be SUPPLY AND STORAGE: Oral: Novartis Pharmaceuticals Canada Inc., Sandoz Canada Inc., Accord Healthcare Inc., and Cobalt Pharmaceuticals Inc. supply Letrozole as mg tablets. Tablets contain lactose. Store at room Pharmascience Inc. supplies Letrozole as mg tablets. Tablets contain lactose and tartrazine. Store at room Teva Canada Limited and Generic Medical Partners supply Letrozole as mg tablets.

8 Tablets contain tartrazine. Store at room ,29 DOSAGE GUIDELINES: Refer to protocol by which patient is being treated. Adults: BCCA usual dose noted in bold, italics Oral: mg PO once daily. Administer with food or on empty Dosage in renal failure: No adjustment required with CrCl > 10 mL/min. Dosing information not available with CrCl < 10 Dosage in hepatic failure: No adjustment required with mild to moderate hepatic dysfunction. Dosing information not available with severe hepatic Dosage in dialysis: no information found REFERENCES: 1. Health Canada Therapeutic Products Programme. Notices of compliance (NOC)-Drugs. Available at: Accessed 15 September, 2000. 2. Health Canada Therapeutic Products Programme. Patent register. Available at: Accessed 15 September, 2000. Letrozole 3. Njar VC, Brodie AM.

9 Comprehensive pharmacology and clinical efficacy of aromatase inhibitors. Drugs 1999;58(2):233-55. 4. Santen RJ, Harvey HA. Use of aromatase inhibitors in breast carcinoma. Endocrine-Related Cancer 1999;6(1):75-92. 5. Lipton A, Demers LM, Harvey HA, et al. Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast Cancer . Cancer 1995;75(8):2132-8. 6. Novartis Pharmaceuticals Canada Inc. Femara product monograph. 5 September 2000. 7. Bajetta E, Zilembo N, Dowsett M, et al. Double-blind, randomised, multicentre endocrine trial comparing two Letrozole doses, in postmenopausal breast Cancer patients. European Journal of Cancer 1999;35(2):208-13. 8. Iveson TJ, Smith IE, Ahern J, et al. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast Cancer .

10 Cancer Research 1993;53(2):266-70. 9. Kvinnsland S, Anker G, Dirix LY, et al. High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast Cancer who had previously failed on tamoxifen treatment. European Journal of Cancer 2000;36(8):976-82. 10. Sioufi A, Gauducheau N, V P, et al. Absolute bioavailability of Letrozole in healthy postmenopausal women. Biopharmaceutics and drug Disposition 1997;18(9):779-89. 11. Sioufi A, Sandrenan N, Godbillon J, et al. Comparative bioavailability of Letrozole under fed and fasting conditions in 12 healthy subjects after a mg single oral administration. Biopharmaceutics and drug Disposition 1997;18(6):489-97. 12. Lamb HM, Adkins JC. Letrozole . A review of its use in postmenopausal women with advanced breast Cancer . Drugs 1998;56(6):1125-40. 13.